Mirtazapine in pregnancy and lactation: A systematic review of adverse outcomes

Anne Ostenfeld; Sofie Lyngholm; Sarah Emilie Christensen; Tonny Studsgaard Petersen; Jon Trærup Andersen; Hanne Brix Westergaard; Lars Henning Pedersen; Ellen Christine Leth Løkkegaard

doi:10.1111/acps.13749

. 2024 Aug 31;151(1):6–32. doi: 10.1111/acps.13749

Mirtazapine in pregnancy and lactation: A systematic review of adverse outcomes

Anne Ostenfeld ^1,^2,^✉, Sofie Lyngholm ^1,², Sarah Emilie Christensen ¹, Tonny Studsgaard Petersen ^2,³, Jon Trærup Andersen ^2,³, Hanne Brix Westergaard ^1,², Lars Henning Pedersen ^4,⁵, Ellen Christine Leth Løkkegaard ^1,²

PMCID: PMC11608810 PMID: 39215625

Abstract

Introduction

Peripartum depression is common and treatment with mirtazapine may be indicated. However, evidence on its safety in pregnancy and lactation is fragmented.

The objective of this systematic review was to evaluate the literature on the safety of mirtazapine in pregnancy and lactation.

Methods

PubMed, Embase, Medline, PsycInfo, and clinicaltrials.gov were searched for ‘antidepressants’ or ‘mirtazapine’ in combination with ‘pregnancy’, ‘lactation’ or ‘offspring’.

No restrictions on type of study were applied and selection was performed by two independent reviewers using Covidence. Two reviewers extracted data and performed risk of bias assessment and evidence synthesis was performed for each outcome individually.

The protocol was registered at PROSPERO (registration number CRD42021275127).

Results

The initial search yielded 15,380 articles after removal of duplicates. After screening based on title and abstract, 431 articles remained for full text review. Of these, 41 studies were included (15 cohort studies, one case–control study, 11 case series, and 14 case reports). In most studies, the outcomes in mirtazapine‐exposed pregnancies were comparable to controls. However, results on congenital malformations and spontaneous abortion were conflicting. Neonatal adaptation syndrome was reported after mirtazapine exposure in late pregnancy. Data on mirtazapine exposure during lactation were scarce.

Conclusions

We identified no substantial evidence indicating that mirtazapine exposure is associated with adverse outcomes in pregnancy or in offspring, other than neonatal adaptation syndrome. However, overall quality of evidence was low, and results on congenital malformations and spontaneous abortions were conflicting. Data on mirtazapine exposure through breastfeeding were limited and did not allow for conclusions.

Keywords: mirtazapine, pregnancy, lactation, fetal safety, offspring safety

Summations

Overall, the identified data on mirtazapine exposure in pregnancy and offspring outcomes were reassuring; however, the quality of evidence was generally low, and results were conflicting regarding risk of spontaneous abortion and congenital malformations.
Awareness should be drawn to risk of neonatal adaptation syndrome after mirtazapine exposure in the last trimester.
Data are limited on mirtazapine exposure through breastfeeding and allow for no conclusions.

Limitations

Overall, quality of evidence was low in the identified studies which included smaller studies, case series and case reports.
Most included studies had a high risk of bias, predominantly due to confounding by indication.
Due to the heterogeneity of the included studies, meta‐analyses were not considered applicable.

1. INTRODUCTION

Major depression disorder (MDD) occurs in approximately 12% of women either in pregnancy or during the postnatal period. ¹ MDD is associated with various adverse outcomes in both the long and short term, ² , ³ and pharmacologic treatment may be required. Mirtazapine is a second‐line treatment approved for MDD, and it may also be effective in treating anxiety disorders and sleep disturbances. ⁴ , ⁵ There is also evidence that mirtazapine has antiemetic effects, ⁶ and case reports have described it as an effective treatment in hyperemesis gravidarum. ⁷ , ⁸

Mirtazapine has affinity for several receptors including α₂‐adrenergic, serotonin 5‐HT_2A, 5‐HT_2C and 5‐HT₃, and histamine H₁‐receptors, ⁵ and its versatile treatment effects make mirtazapine an advantageous treatment option for some patients.

However, pharmacologic treatment during pregnancy and lactation remains challenging due to uncertainties concerning fetal safety. While safety of the most frequently used antidepressants, selective serotonin reuptake inhibitors (SSRIs), has been investigated in numerous studies, there is limited evidence available regarding the safety of mirtazapine use in pregnancy and lactation.

A systematic review performed in 2016 included 390 exposed neonates and several outcomes. ⁹ However, more data has been published since then, and associations with additional outcomes have been investigated.

In the 2016 review, the authors found “no data that suggests an absolute contraindication for the use of mirtazapine in pregnancy”; however, they concluded that the safety could not be assessed properly due to lack of data. ⁹ Similarly, no definite conclusions could be drawn regarding neonatal complications or the safety of mirtazapine during lactation.

The aim of this study was to perform an updated systematic review summarising the evidence on the safety of mirtazapine exposure in pregnancy and lactation. We aimed to identify all available literature on women exposed to mirtazapine during pregnancy and/or lactation with at least one reported outcome of the pregnancy and/or the offspring. All available outcomes and all study designs including case reports were included so as to capture all possible adverse outcomes.

No patients were involved in the study development.

2. MATERIALS AND METHODS

The protocol for this review was registered with PROSPERO (CRD42021275127) and the review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) guideline. ¹⁰

2.1. Eligibility, sources, and search strategy

Studies were considered eligible for inclusion if they contained original data on mirtazapine‐exposed pregnancies or infant exposure through lactation, and if pregnancy or offspring outcomes were reported. All study types were included, and pregnancy and offspring outcomes were not prespecified in either character or length of follow‐up so as to ensure that even unforeseen adverse outcomes were captured.

Studies were excluded if mirtazapine‐exposed pregnancies were pooled with pregnancies exposed to other antidepressants and the outcomes were not separately reported for the mirtazapine‐exposed sub‐population.

A digital search of the databases PubMed, Embase, Medline, and PsycInfo was conducted in August 2020. The search strategy included ‘antidepressants’ or ‘mirtazapine’ in combination with ‘pregnancy’, ‘lactation’, or ‘offspring’. The full search strategy can be found in the supplementary material. Articles were included in English, Spanish, German, Dutch, Danish, Swedish, and Norwegian if published during or after 1992, when mirtazapine was initially approved. All included articles were cross‐referenced for further possible relevant articles.

An additional search in clinicaltrials.gov was performed with the terms ‘pregnancy’ or ‘breast feeding’ as the condition and ‘mirtazapine’ as the intervention.

2.2. Selection process

Study selection was performed using Covidence, and duplicates were removed. The identified studies were then screened by two independent reviewers (AO and SL) based on title and abstract, and disagreements were solved by consensus. The full texts of the selected studies were then independently assessed by AO and SL, and again disagreements were resolved by consensus.

2.3. Data extraction and risk of bias assessment

Two independent reviewers (AO and SEC) extracted data to a premade template including author, year of publication, study design, number of exposed, control group (where applicable), outcome, and other variables.

Risk of bias was assessed using the Risk Of Bias In Non‐randomised Studies of Interventions (ROBINS‐I) tool. ¹¹ , ¹² The tool includes assessments of bias in the following domains: confounding, selection of participants into the study, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of reported results. However, due to the nature of the included studies and the intervention and outcomes investigated, the domain ‘deviations from intended interventions’ was not applicable and thus omitted from the assessment of risk of bias.

Risk of bias and direction of bias were assessed independently by AO and SEC, and disagreements were resolved by consensus.

2.4. Evidence synthesis

Evidence synthesis was performed for each outcome individually based on the studies reporting on that specific outcome.

2.5. Specification of relevant exposure and outcomes

For the outcome congenital malformations, relevant exposure was limited to the first trimester of pregnancy. Mirtazapine exposure was not considered a possible cause of chromosomal or genetic anomalies, as it is not mutagenic. ¹³ Malformations due to chromosomal or genetic anomalies were therefore excluded from the evidence synthesis when specified.

Only third trimester mirtazapine exposure was considered relevant for the development of neonatal adaptation syndrome (NAS), also known as neonatal abstinence syndrome. The syndrome is characterised by transient adverse effects in the neonate following intrauterine exposure to psychoactive drugs including antidepressants. Symptoms include respiratory distress, feeding difficulties, sleep problems, irritability, jitteriness, tremors, rigidity, shivering, restlessness, temperature instability, jaundice, and hypoglycaemia. ¹⁴

3. RESULTS

The initial search yielded 15,380 publications after duplicates were removed. Following screening of title and/or abstract, 431 publications were considered eligible for full text assessment and two additional publications were identified from references from other studies. In total, 41 articles were eligible for inclusion. The study selection process is shown in Figure 1.

3.1. Study characteristics

All included studies were observational, although very heterogeneous in design and outcomes.

Of the 41 studies meeting inclusion criteria, 15 were cohort studies, 1 a case–control study, 11 were case series, and 14 were individual case reports (Table 1). Studies were regarded as case series if they did not contain a control group. Thus, one study described as a case–control study by the authors was reclassified as a case series, because it did not contain a control group. ¹⁵

TABLE 1.

Included studies.

Author, year	Data source	Number of mirtazapine‐exposed pregnancies (infants)	Time of exposure	Control group	Outcome of interest
Cohort studies
Djulus et al., 2006 ²²	Teratology information service in Canada, US, Italy, UK, and Australia, 2002–2005.	104 (77)	1st, 2nd, and 3rd trimester	(A) Exposed to other antidepressants and (B) Unexposed. Both matched on other factors.	Spontaneous abortion, termination of pregnancy, stillbirth, live birth, gestational age at delivery, preterm birth, birth weight, congenital malformations.
Einarson et al., 2009 ²⁸	Teratogen advice services in Canada, years not specified.	(68)	1st trimester	Teratogen‐non‐exposed, matched on several factors.	Congenital malformations.
Güngör et al., 2019 ²⁹	Teratology information service 2015–2018, country not specified. Authors from Turkey.	34 (34)	1st, 2nd, and 3rd trimester, and lactation	(A) SSRI‐exposed, (B) Non‐exposed with psychiatric diagnoses.	Gestational age at delivery, mode of delivery, birth weight, preterm birth, length of stay in neonatal care unit, occurrence of breastfeeding.
Källén et al., 2013 ²⁶	National registers in Sweden between 1996 and 2011.	(585)	1st, 2nd, and 3rd trimester	Background population adjusted for other factors.	Congenital malformations.
Kieviet et al., 2015 ³⁰	Hospital records from one hospital in the Netherlands, 2007–2012.	(35)	3rd trimester	Exposed to other antidepressants.	Poor neonatal adaptation.
Kieviet et al., 2017 ⁴³ (likely overlapping with Kieviet et al., 2015)	One maternity ward in the Netherlands, 2012–2013.	(10)	3rd trimester		Poor neonatal adaptation.
Kjaersgaard et al., 2013 ²⁰	National registers in Denmark, 1997–2008.		1st, 2nd, and 3rd trimester	Background population.	Spontaneous abortion.
Lennestål et al., 2007 ²⁷ (considered to be included in Källén et al., 2013)	National registers in Sweden until 2004 (initial year not specified).	153 (154)	1st, 2nd, and 3rd trimester	Background population.	Congenital malformations (other outcomes not specified for mirtazapine exposure).
Ozturk et al., 2016 ²³	Prenatal consultation service for psychotropic drug exposure in Turkey, 2007–2012.	7 (7)	Pregnancy (trimester not specified)	Teratogen non‐exposed.	Spontaneous abortion/ stillbirth, live birth, preterm birth, congenital malformations.
Palmsten et al., 2013a ³³	Insurance‐based register in the US, 2000–2007.	253	2nd and 3rd trimester	Non‐exposed diagnosed with depression.	Preeclampsia.
Palmsten et al., 2013b ³⁴	Insurance‐based register in the US, 2000–2007.	321	5 months prior to delivery or later	Non‐exposed diagnosed with mood or anxiety disorder.	Postpartum haemorrhage.
Viktorin et al., 2017 ³²	National registers in Sweden of children born in 2006–2007.	(62)	1st, 2nd, and 3rd trimester	(A) Background population, (B) Sub‐analysis of maternal diagnosis of anxiety or depression.	Autism spectrum disorder at 7–8 years of age.
Wachman et al., 2018 ⁴⁴	Substance abuse centre in the US, 2006–2015.	(37)	At delivery	Mirtazapine unexposed (all had been exposed to opioids).	Neonatal abstinence syndrome severity.
Winterfeld et al., 2015 ²¹	11 European teratology information services, 1995–2011.	357 (290)	1st, 2nd, and 3rd trimester	(A) SSRI‐exposed, (B) Non‐exposed.	Spontaneous abortion/ stillbirth, termination of pregnancy, live birth, birth weight, gestational age at delivery, preterm birth, congenital malformations, infant development, and other anomalies.
Yaris et al., 2005 ¹⁸ , ^a (considered to be included in 2004a)	Teratology information service in Turkey, 1999–2004.	7 (7)	1st trimester	Unexposed.	Spontaneous abortion, stillbirth, preterm birth, congenital malformations, and infant development at 12 months.
Case–control study
Kieler et al., 2005 ²⁵	National registers in Denmark, Norway, and Finland 1996–2007.	164	1st and 2nd trimester	Background ongoing pregnancies.	Late termination of pregnancy (gestational week 12–23), late termination of pregnancy for fetal anomalies.
Case reports and case series
Aichorn et al., 2004 ³⁷	Austria	(1)	Lactation		Infant development at 20 weeks (mirtazapine concentration in milk and maternal and infant plasma).
Arshad et al., 2017 ⁴⁵	UK	1 (1)	1st trimester		Gestational age at delivery, mode of delivery, birth weight, APGAR, cord artery pH and base excess, healthy infant at birth.
Biswas et al., 2003 ¹⁵ , ^b	Questionnaires sent to GPs prescribing mirtazapine in the UK identified via prescription register, Sep 1997 – Feb 1999.	41 (24)	1st trimester		Spontaneous abortion, termination of pregnancy, live births, congenital malformations.
Dorn et al., 2002 ⁴⁶	Germany	1 (1)	2nd trimester		Gestational age at delivery, healthy infant at birth.
Gentile et al., 2015 ⁴⁷	Italy	1 (1)	1st, 2nd, and 3rd trimester		Gestational age at delivery, mode of delivery, birth weight, APGAR, healthy infant at birth, infant development at 4 months.
Guclu et al., 2005 ⁴⁸	Turkey	3 (3)	1st trimester		Gestational age at delivery, mode of delivery, healthy infant at birth, ultrasound, infant morphology, and development at 12 months.
Habermann et al., 2013 ¹⁶ , ^c	Teratology information service in Germany, 1997–2009.	1 (1)	1st trimester		Gestational age at delivery, neonatal death.
Källén et al., 2008 ¹⁷ , ^c	National registers in Sweden, 1997–2005.	1 (1)	Pregnancy (trimester not specified)		Persistent pulmonary hypertension of the neonate.
Kesim et al., 2002 ⁴⁹	Turkey	2 (2)	1st trimester		Gestational age at delivery, mode of delivery, birth weight, APGAR, neonatal hyperbilirubinemia, congenital malformations, and infant development at 6 months.
Klier et al., 2007 ³⁸	Austria/Canada	(1)	Lactation		Infant development at 6 months (mirtazapine concentration in milk and maternal and infant plasma).
Kristensen et al., 2007 ³⁵	Australia	(8)	Lactation		Infant development (mirtazapine concentration in milk and maternal and infant plasma).
Lieb et al., 2012 ⁵⁰	Germany	1	2nd, 3rd trimester		Gestational age at delivery, mode of delivery.
Omay et al., 2017 ⁸	France/Canada	5 (4)	1st, 2nd, and 3rd trimester		Termination of pregnancy (1 trisomy for 18), delivery at term (1 reported gestational age at delivery and mode of delivery), infant development at follow‐up (time unknown)
Rohde et al., 2003 ⁵¹	Germany	1 (2)	1st, 2nd, and 3rd trimester		Gestational age at delivery, mode of delivery, birth weight, APGAR, infant development at 6 months.
Saks, 2001 ⁵²	US	7 (7)	1st, 2nd, and 3rd trimester		Gestational age at delivery, mode of delivery, birth weight, APGAR, healthy infant at birth (1 follow‐up at 2 years), pregnancy complication (1), neonatal complication (1)
Schwarzer et al., 2008 ⁵³	Germany	1 (1)	2nd and 3rd trimester		Preeclampsia with intrauterine growth restriction, gestational age at delivery, mode of delivery, birth weight, APGAR, cord artery pH, congenital malformations, neonatal abstinence syndrome.
Simhandl et al., 1999 ⁵⁴	Austria.	1 (1)	1st trimester		Gestational age at delivery birth weight, APGAR, healthy infant at birth.
Smit et al., 2015 ³¹	Psychiatric‐obstetric‐paediatric clinic in Holland, 2007–2012.	56 (56)	1st, 2nd, 3rd trimester and lactation		Gestational age at delivery, mode of delivery, birth weight, preterm birth, neonatal complications including poor neonatal adaptation, congenital malformations, feeding and sleeping problems in infants ≥2 days postpartum.
Sokolover et al., 2008 ⁵⁵	Israel	1 (2)	1st, 2nd, and 3rd trimester		Gestational age at delivery, mode of delivery, birth weight, APGAR, neonatal hypothermia, infant development at 4 months.
Tonn et al., 2009 ³⁹	Germany	1 (1)	1st, 2nd, 3rd trimester, and lactation		Birth weight, possible sedation, infant development at 2 months (mirtazapine concentration in milk and maternal and infant plasma).
Uguz, 2013 ⁵⁶	Turkey	3 (3)	2nd and 3rd trimester		Gestational age at delivery, mode of delivery, birth weight, healthy infant at birth, neonatal tachycardia.
Uguz, 2014 ⁵⁷	Turkey	2 (2)	2nd and 3rd trimester		Gestational age at delivery, mode of delivery, birth weight, healthy infant at birth.
Uguz, 2019 ³⁶	Turkey	(8)	Lactation		Adverse events in infants.
Yaris et al., 2004a ¹⁹	Teratology information service in Turkey, years not specified.	9 (7)	1st trimester		Spontaneous abortion, termination of pregnancy, live birth, birth weight, APGAR, gestational age at delivery, mode of delivery, healthy infant at birth, infant development at 12 months.
Yaris et al., 2004b ²⁴ (Included in case series Yaris et al., 2004a)	Turkey	1 (1)	1st trimester		Gestational age at delivery, mode of delivery, birth weight, APGAR, infant development at 6 months.

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^{^a}

Authors defined the study as a case–control study; however, the study design is that of a cohort study and has therefore been regarded as such.

^{^b}

Authors defined the study as a cohort study; however, the study has been regarded as a case series in this review, as it did not contain a control group.

^{^c}

Case report derived from a cohort study which did not meet inclusion criteria.

Two of the case reports were derived from cohort studies which did not meet inclusion criteria because the outcome was not separately analysed for the mirtazapine‐exposed group. However, a specific mirtazapine‐exposed pregnancy with an adverse outcome was described in each of these two studies, and these two pregnancies were therefore included as case reports. ¹⁶ , ¹⁷

In total we identified data on 2343 mirtazapine‐exposed pregnancies and 63 infants exposed through breast milk. However, there is likely to be a substantial overlap in the included pregnancies, and different studies have observed entirely or partially the same pregnancies with focus on either the same or different outcomes. This was recorded, and the authors were contacted for clarification.

The data included in the case series and the cohort study comprising nine pregnancies published by Yaris et al. ¹⁸ , ¹⁹ is assumed to be overlapping; however, this could not be confirmed by the authors. The data will be referred to as contained in the cohort study, with data from the case series providing supplementary information. Risk of bias assessment using the ROBINS‐I tool is shown in Table 2.

TABLE 2.

Risk of bias for included studies.

Author, year	Confounding	Selection of participants	Classification of interventions	Missing data	Measurement of outcomes	Selection of reported results	Overall	Direction of bias (most important bias)
Cohort studies
Djulus et al., 2006	Serious	Serious	Moderate	No info	Moderate	Moderate	Serious	Away from null (confounding by indication)
Einarson et al., 2009	Critical	Serious	Moderate	No info	Moderate	Serious	Critical	Away from null (confounding by indication)
Güngör et al., 2019	Serious	Low	Moderate	No info	Serious	Moderate	Serious	Away from null (confounding by indication)
Källén et al., 2013	Critical	Low	Low	No info	Moderate	Moderate	Critical	Away from null (confounding by indication)
Kieviet et al., 2015	Moderate	Serious	Serious	Low	Moderate	Moderate	Serious	Away from null (measure of outcomes)
Kieviet et al., 2017	Moderate	Serious	Moderate	Low	Moderate	Moderate	Serious	Away from null (measure of outcomes)
Kjaersgaard et al., 2013	Serious	Low	Low	Low	Low	Moderate	Serious	Away from null (confounding by indication)
Lennestål et al., 2007	Critical	Low	Low	Low	Moderate	Moderate	Critical	Away from null (confounding by indication)
Ozturk et al., 2016	Critical	Serious	Moderate	Low	Moderate	Moderate	Critical	Away from null (confounding by indication)
Palmsten et al., 2013a	Serious	Low	Low	Low	Low	Moderate	Serious	Away from null (confounding by indication)
Palmsten et al., 2013b	Serious	Low	Low	Low	Low	Moderate	Serious	Away from null (confounding by indication)
Viktorin et al., 2017	Moderate	Low	Low	Low	Low	Low	Moderate	Away from null (confounding by indication)
Wachman et al., 2018	Serious	Low	Serious	No info	Low	Moderate	Serious	Away from null (confounding by indication)
Winterfeld et al., 2015	Serious	Serious	Moderate	Serious	Moderate	Moderate	Serious	Away from null (confounding by indication)
Yaris et al., 2005	Critical	Serious	Moderate	Serious	Moderate	Serious	Critical	Unpredictable
Case–control study
Kieler et al., 2005	Critical	Low	Low	No info	Low	Moderate	Critical	Away from null (confounding by indication, classification of intervention, and outcome)
Aichorn et al., 2004	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Case series and case reports
Arshad et al., 2017	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Biswas et al., 2003	Critical	Serious	Low	Serious	Moderate	Serious	Critical	Away from null (confounding by indication, selection bias)
Dorn et al., 2002	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Gentile et al., 2015	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Guclu et al., 2005	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Habermann et al., 2013	Critical	Critical	Low	N/A	N/A	Critical	Critical	Away from null (selection bias)
Källén et al., 2008	Critical	Critical	Low	N/A	N/A	Critical	Critical	Away from null (selection bias)
Kesim et al., 2002	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Klier et al., 2007	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Kristensen et al., 2007	Critical	No info	Low	Moderate	Low	Moderate	Critical	Away from null (confounding by indication)
Lieb et al., 2012	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Omay et al., 2017	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Rohde et al., 2003	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Saks, 2001	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Schwarzer et al., 2008	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Simhandl et al., 1999	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Smit et al., 2015	Critical	Serious	Moderate	Low	Low	Serious	Critical	Away from null (confounding by indication)
Sokolover et al., 2008	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Tonn et al., 2009	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Uguz et al., 2013	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Uguz et al., 2014	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Uguz et al., 2019	Critical	Critical	Low	Low	N/A	Critical	Critical	Unpredictable
Yaris et al., 2004a	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable
Yaris et al., 2004b	Critical	Critical	Low	N/A	N/A	Critical	Critical	Unpredictable

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3.2. Outcomes

Data on all outcomes are summarised in Table 3.

TABLE 3.

Outcomes reported in included studies.

Author	Study design and data origin	Outcome		Estimate	Comment
Author	Study design and data origin	Mirtazapine exposed	Control group	Estimate	Comment
Spontaneous abortion
Kjaersgaard et al.	Cohort from national registers.		Background population.	RR 1.73 (95% CI 1.46–2.04)	Unadjusted analysis.
Kjaersgaard et al.	Cohort from national registers.		Background population.	RR 2.23 (95% CI 1.34–3.70)	Unadjusted analysis restricted to pregnancies with hospital diagnosis of depression.
Winterfeld et al.	Cohort from teratogen information service.	39/323 (12.1%)	41/342 (12.0%) SSRI‐exposed.	OR 1.01 (95% CI 0.63–1.61)	Composite outcome including spontaneous abortion and stillbirth. Unadjusted analyses.
Winterfeld et al.	Cohort from teratogen information service.	39/323 (12.1%)	31/333 (9.3%) Unexposed.	OR 1.34 (95%. CI 0.81–2.20)
Djulus et al.	Cohort from teratogen information service.	20/104 (19.2%)	18/104 (17.3%). Antidepressant‐exposed.
Djulus et al.	Cohort from teratogen information service.	20/104 (19.2%)	11/104 (10.6%) Unexposed.
Yaris et al.	Cohort from teratogen information service.	1/9 (11.1%)	9/167 (5.4%) Unexposed.
Ozturk et al.	Cohort from prenatal consultation service.	1/7 (14.3%)	15/275 (5.5%) Unexposed.
Biswas et al.	Case series from questionnaires filled by GPs prescribing mirtazapine.	8/41 (19.5%)	None.
Elective termination of pregnancy (TOP)
Winterfeld et al.	Cohort from teratogen information service.	28/357 (7.8%)	12/357 (3.4%) SSRI‐exposed.	OR 2.45 (95% CI 1.22–4.89)	Unadjusted analyses.
Winterfeld et al.	Cohort from teratogen information service.	28/357 (7.8%)	20/357 (5.6%) Unexposed.	OR 1.34 (95%. CI 1.43–2.60)	Unadjusted analyses.
Yaris et al.	Cohort from teratogen information service.	1/9 (1.1%)	3/167 (18.0%) Unexposed.
Ozturk et al.	Cohort from prenatal consultation service.	2/7 (28.6%)	14/275 (5.1%) Unexposed.
Biswas et al.	Case series from questionnaires filled by GPs prescribing mirtazapine.	8/41 (19.5%)	None.
Therapeutic TOP. There was inconsistent reporting of reason for TOP, which in some cases included maternal factors.
Kieler et al.	Case–control from national registers.	34 cases (2.3 mirtazapine‐exposed/1000 cases).	130 controls (0.9 mirtazapine‐exposed /1000 controls).	OR 2.6 (95% CI 1.8–3.9)	Late termination of pregnancy for any reason, maternal or feta. (gestational week 12–23). Analysis adjusted for gestational age, country, year, maternal age, parity and selected comedications.
Winterfeld et al.	Cohort from teratogen information service.	5/357 (1.4%)	2/357 (0.6%) SSRI‐exposed.	OR 2.52 (95% CI 0.49–13.08)	Reason for TOP not specified for all cases. Unadjusted analyses.
Winterfeld et al.	Cohort from teratogen information service.	5/357 (1.4%)	4/357 (1.1%) Unexposed.	OR 1.25 (95%. CI 0.33–4.71)
Djulus et al.	Cohort from teratogen information service.	6/104 (5.8%)	3/104 (2.9%) Antidepressant‐exposed.
Djulus et al.	Cohort from teratogen information service.	6/104 (5.8%)	1/104 (1.0%) Unexposed.
Omay et al.	Case series.	1/5 (due to trisomy 18)	None.
Stillbirth
Winterfeld et al.	Cohort from teratogen information service.	39/323 (12.1%)	41/342 (12.0%) SSRI‐exposed.	OR 1.01 (95% CI 0.63–1.61)	Composite outcome including spontaneous abortion and stillbirth. Unadjusted analyses.
Winterfeld et al.	Cohort from teratogen information service.	39/323 (12.1%)	31/333 (9.3%) Unexposed.	OR 1.34 (95%. CI 0.81–2.20)
Djulus et al.	Cohort from teratogen information service.	1/78 (1.3%)	0/83 (0%) Antidepressant‐exposed.
Djulus et al.	Cohort from teratogen information service.	1/78 (1.3%)	0/92 (0%) Unexposed.
Yaris et al.	Cohort from teratogen information service.	0/7 (0%)	0/155 (0%) Unexposed.
Ozturk et al.	Cohort from prenatal consultation service.	0/4 (0%)	0/275 (0%) Unexposed.
Biswas et al.	Case series from questionnaires filled by mirtazapine prescribing GPs.	8/41 (19.5%)	None.
Arshad et al., Dorn et al., Gentile et al., Guclu et al., Kesim et al., Omay et al., Rohde et al., Saks, Schwarzer et al., Simhandl et al., Sokolover et al., Uguz, Uguz.	Various case series and case reports describing mirtazapine‐exposed pregnancies.	0/30*			*Due to selective reporting in case reports, this result could be substantially biased.
Live births (reason for pregnancies not ending in live birth may include elective termination of pregnancy)
Winterfeld et al.	Cohort from teratogen information service.	290/357 (81%)	306/357 (86%) SSRI‐exposed.	OR 0.72 (95% CI 0.49–1.06).	Unadjusted analyses.
Winterfeld et al.	Cohort from teratogen information service.	290/357 (81%)	308/357 (86%) Unexposed.	OR 0.72 (95% CI 0.49–1.06).	Unadjusted analyses.
Djulus et al.	Cohort from teratogen information service.	77/104 (74%)	83/104 (80%) Antidepressant‐exposed.	p = 0.41	Unadjusted analyses.
Djulus et al.	Cohort from teratogen information service.	77/104 (74%)	92/104 (88%) Unexposed.	p = 0.01	Unadjusted analyses.
Yaris et al.	Cohort from teratogen information service.	7/9 (78%)	155/167 (93%) Unexposed.
Ozturk et al.	Cohort from prenatal consultation service.	4/7 (57%)	246/275 (89%) Unexposed.
Biswas et al.	Case series from questionnaires filled by mirtazapine prescribing GPs.	24/41 (59%)	None.
Arshad et al., Dorn et al., Gentile et al., Guclu et al., Habermann et al., Källén et al., Kesim et al., Omay et al., Rohde et al., Saks, Schwarzer et al., Simhandl et al., Smit et al., Sokolover et al., Tonn et al., Uguz, Uguz.	Various other studies including cohorts comprised of live births, case series, and case reports.	224/225 (226 infants)*			*Due to inclusion criteria in cohort studies and selective reporting in case reports, this result should be considered to be substantially biased.
Gestational age at delivery
Winterfeld et al.	Cohort from teratogen information service.	39 (38–40)	39 (38–40) SSRI‐exposed.		Median (inter quartile range), weeks.
Winterfeld et al.	Cohort from teratogen information service.	39 (38–40)	39 (38–40) Unexposed.		Median (inter quartile range), weeks.
Djulus et al.	Cohort from teratogen information service.	38.9 ± 2.5	39.1 ± 1.8 Antidepressant‐exposed.		Mean ± SD, weeks.
Djulus et al.	Cohort from teratogen information service.	38.9 ± 2.5	39.6 ± 1.4 Unexposed.		Mean ± SD, weeks.
Güngör et al.	Cohort from teratogen information service.	38.99 ± 1.37 Mirtazapine‐exposed.	38.43 ± 1.23 SSRI‐exposed.		Mean ± SD, weeks.
		38.35 ± 1.40 Mirtazapine‐SSRI‐exposed.	38.09 ± 2.73 Unmedicated with psychiatric diagnosis.
		38.35 ± 1.40 Mirtazapine‐SSRI‐exposed.	38.76 ± 1.70 Healthy controls.
Smit et al.	Case series from psychiatric‐obstetric‐paediatric clinic.	39.3 ± 1.7	None.		Mean ± SD, weeks.
Preterm birth (gestational age < 37 weeks)
Winterfeld et al.	Cohort from teratogen information service.	31/279 (11.1%)	32/302 (10.6%) SSRI‐exposed.
Winterfeld et al.	Cohort from teratogen information service.	31/279 (11.1%)	26/309 (8.6%) Unexposed.
Djulus et al.	Cohort from teratogen information service.	10/77 (13%)	7/83 (7%) Antidepressant‐exposed.
Djulus et al.	Cohort from teratogen information service.	10/77 (13%)	2/92 (2%) Unexposed.
Güngör et al.	Cohort from teratogen information service.	6% Mirtazapine‐exposed.	7% SSRI‐exposed.
		5% Mirtazapine‐SSRI‐exposed.	4% Unmedicated with psychiatric diagnosis.
		5% Mirtazapine‐SSRI‐exposed.	4% Healthy controls.
Yaris et al.	Cohort from teratogen information service.	0/7 (0%)	3/155 (1.9%) Unexposed.
Ozturk et al.	Cohort from prenatal consultation service.	0/4 (0%)	8/246 (3.2%) Unexposed.
Smit et al.	Case series from psychiatric‐obstetric‐paediatric clinic.	5/56 (8.9%)	7.7% Background population in the Netherlands.
Biswas et al.	Case series from questionnaires filled by GPs who prescribe mirtazapine.	4/24 (16.7%)	None.
Arshad et al., Dorn et al., Gentile et al., Guclu et al., Habermann et al., Kesim et al., Omay et al., Rohde et al., Saks, Schwarzer et al., Simhandl., al., Sokolover et al., Uguz.	Case reports and case series.	8/27 (30%)	None.
Birth weight
Winterfeld et al.	Cohort from teratogen information service.	3320 (2979–3636)	3230 (2910–3629) SSRI‐exposed.		Median (inter quartile range), grams.
Winterfeld et al.	Cohort from teratogen information service.	3320 (2979–3636)	3338 (2967–3650) Unexposed.		Median (inter quartile range), grams.
Djulus et al.	Cohort from teratogen information service.	3335 ± 654	3419 ± 597 Antidepressant‐exposed.		Mean ± SD, g.
Djulus et al.	Cohort from teratogen information service.	3335 ± 654	3502 ± 540 Unexposed.		Mean ± SD, g.
Güngör et al.	Cohort from teratogen information service.	3251 ± 502 Mirtazapine‐exposed.	3153 ± 435 SSRI‐exposed.		Mean ± SD, g.
		3191 ± 437 Mirtazapine‐SSRI‐exposed.	3052 ± 636 Unmedicated with psychiatric diagnosis.
		3191 ± 437 Mirtazapine‐SSRI‐exposed.	3194 ± 613 Healthy controls.
Smit et al.	Case series from psychiatric‐obstetric‐paediatric clinic.	3433 ± 470	None.		Mean ± SD, g.
Small for gestational age
Güngör et al.	Cohort from teratogen information service.	7% Mirtazapine‐exposed.	10% SSRI‐exposed.
		6% Mirtazapine‐SSRI‐exposed.	14% Unmedicated with psychiatric diagnosis.
		6% Mirtazapine‐SSRI‐exposed.	8% Healthy controls.
Smit et al.	Case series from psychiatric‐obstetric‐paediatric clinic.	3/56 (4.5%)	None.
Large for gestational age
Güngör et al.	Cohort from teratogen information service.	0% Mirtazapine‐exposed.	5% SSRI‐exposed.
		6% Mirtazapine‐SSRI‐exposed.	0% Unmedicated with psychiatric diagnosis.
		6% Mirtazapine‐SSRI‐exposed.	6% Healthy controls.
Smit et al.	Case series from psychiatric‐obstetric‐paediatric clinic.	7/56 (12.5%)	None.
Congenital malformations
Källén et al.	Cohort from national registers.	Severe malformation after 1st trimester exposure: 20/585 (3.4%).	Background population.	OR 1.10 (95% CI 0.70–1.71)	Not described if analyses were adjusted.
		Any cardiac defect after 1st trimester exposure: 7/585 (1.2%).		RR 1.06 (95% CI 0.42–2.19)
		Septum defect after 1st trimester exposure: 6/585 (1.0%).		RR 1.22 (95% CI 0.45–2.65)
Lennestål et al. (may be included in Källén et al.)	Cohort from national registers.	5/154 (3.2%): 2 ventricular septum defects, 1 atrium septum defect (also exposed to venlafaxine), 1 median cleft palate, 1 hypospadias.	4.7% in the background population.		Congenital malformations after 1st trimester exposure.
Kieler et al.	Case–control study from national registers.	9 cases (1.6 mirtazapine‐exposed/1000 cases).	83 controls (0.8 mirtazapine‐exposed /1000 controls).	OR 2.2 (95% CI 1.1–4.5, 99% CI 0.9–5.7)	Late termination of pregnancy due to fetal anomaly (may include chromosomal and genetic anomalies). Exposure not restricted to 1st trimester. Analyses adjusted for gestational age, country, year, maternal age, parity, and selected comedications.
Winterfeld et al.	Cohort from teratogen information service.	10/292 (3.4%): 3 septal heart defects, 1 pulmonic stenosis, patent foramen ovale and pilonidal sinus, 1 cleft palate, 1 infant with kidney cysts, 2 polydactyly (1 also exposed to valproate, venlafaxine, and chlorpromazine), 1 acrania, 1 trisomy 21.	13/307 (4.2%) SSRI‐exposed.	Major malformations OR 0.80 (95% CI 0.35–1.86).	Major birth defects after 1st trimester exposure, excluding genetic or chromosomal. Analyses adjusted for comedication.
Winterfeld et al.	Cohort from teratogen information service.		6/309 (1.9%) Unexposed.	Major malformations OR 1.79 (95% CI 0.64–4.99).
Djulus et al.	Cohort from teratogen information service.	2/77 (2.6%): 1 patent ductus arteriosus, 1 midline facial defect.	1/83 (1.2%) Antidepressant‐exposed.		Major malformations. 95% had been exposed in the 1st trimester.
Djulus et al.	Cohort from teratogen information service.		2/92 (2.2%) Unexposed.
Einarson et al.	Cohort from teratogen information service.	2/68 (2.9%): 1 tracheomalacia, 1 vesicourethral reflux.	22/860 (2.6%) Antidepressant‐exposed.		Major malformations after 1st trimester exposure.
Einarson et al.	Cohort from teratogen information service.	2/68 (2.9%): 1 tracheomalacia, 1 vesicourethral reflux.	25/928 (2.7%) Unexposed.		Major malformations after 1st trimester exposure.
Yaris et al.	Cohort from teratogen information service.	0/7 (0%)	1/155 (0.6%) Unexposed.		Malformations after 1st trimester exposure.
Ozturk et al.	Cohort from prenatal consultation service.	0/4 (0%)	3/246 (1.2%) Unexposed.		Malformations, exposure time not specified.
Smit et al.	Case series.	0/26 (0%)	None.		Malformations after 1st trimester exposure.
Biswas et al.	Case series from questionnaires filled by mirtazapine prescribing GPs.	1/24 (4.2%): 1 patent ductus arteriosus.	None.		Malformations, exposure time not specified.
Arshad et al., Gentile et al., Guclu et al., Habermann et al., Kesim et al., Omay et al., Rohde et al., Saks, Simhandl et al., Sokolover et al., Tonn et al.	Various case series and case reports describing pregnancies exposed in the first trimester.	0/22*	None.		Malformations after 1st trimester exposure, excluding chromosomal. *Due to selective reporting in case reports, this result should be considered to be substantially biased.
Neonatal complications
Güngör et al.	Cohort from teratogen information service.	12% Mirtazapine‐exposed.	17% SSRI‐exposed.		Stay at neonatal intensive care unit.
		16% Mirtazapine‐SSRI‐exposed.	13% Unmedicated with psychiatric diagnosis.
		16% Mirtazapine‐SSRI‐exposed.	30% Healthy controls.
Güngör et al.	Cohort from teratogen information service.	1.3 ± 3.0 Mirtazapine‐exposed.	1.1 ± 3.0 SSRI‐exposed.		Length of stay at neonatal intensive care unit (days).
		0.6 ± 1.8 Mirtazapine‐SSRI‐exposed.	4.2 ± 18.8 Unmedicated with psychiatric diagnosis.
		0.6 ± 1.8 Mirtazapine‐SSRI‐exposed.	3.0 ± 7.6 Healthy controls.
Wachman et al.	Cohort from substance abuse centre.	23.5 Mirtazapine‐opioid‐exposed.	19.9 Opioid‐exposed.		Length of postnatal hospital stay (days).
Kieviet et al.	Cohort from maternity ward.	18/35 (51%).	128/188 (68%) SSRI‐exposed.	0.50 (95% CI 0.24–1.03).	Neonatal adaptation syndrome. Unadjusted analysis.
Smit et al.	Case series from psychiatric‐obstetric‐paediatric clinic.	14/54 (26%) Including 1 case of respiratory distress.	None.		Neonatal adaptation syndrome.
Kieviet et al.	Cohort study from maternity ward.	2/7 (29%) Mirtazapine‐exposed.	None.		Neonatal adaptation syndrome.
Kieviet et al.	Cohort study from maternity ward.	1/3 (33%) Mirtazapine‐SSRI‐exposed.	None.		Neonatal adaptation syndrome.
Güngör et al.	Cohort from teratogen information service.	18% Mirtazapine‐exposed.	48% SSRI‐exposed.		Hyperbilirubinaemia.
		22% Mirtazapine‐SSRI‐exposed.	46% Unmedicated with psychiatric diagnosis.
		22% Mirtazapine‐SSRI‐exposed.	18% Healthy controls.
Smit et al.	Case series from psychiatric‐obstetric‐paediatric clinic.	3/56 (5.4%)	None.		Hyperbilirubinaemia.
Smit et al.	Case series from psychiatric‐obstetric‐paediatric clinic.	Additional outcomes among the 56 neonates: Fetal distress during childbirth (n = 6) Infection (n = 3) PPHN (n = 1; resolved within hours without treatment) Asphyxia (n = 0) Hypoglycaemia (n = 0) Hypothermia (n = 0)
Arshad et al., Dorn et al., Gentile et al., Guclu et al., Källén et al., Kesim et al., Rohde et al., Saks, Schwarzer et al., Simhandl et al., Sokolover et al, Tonn et al., Uguz, Uguz, Yaris et al.	Case reports and case series.	Additional outcomes among 32 neonates: NAS (n = 1) PPHN (n = 2) Hypothermia (n = 2, twins born at 35 weeks) Tachypnoea (n = 1) Hyperbilirubinemia (n = 1) Mild gastro‐oesophageal reflux (n = 1)
Infant death
Habermann et al.	Case report.	1/1			Neonatal death (infant born in gestational week 32 and suffered asphyxia and pneumonia, died one day postpartum).
Winterfeld et al.	Cohort from teratogen information service.	1/290 (0.3%)	0/306 SSRI‐exposed.		Death at 6 months (child born with cardiomyopathy).
Winterfeld et al.	Cohort from teratogen information service.	1/290 (0.3%)	0/308 Unexposed.		Death at 6 months (child born with cardiomyopathy).
Offspring development
Winterfeld et al.	Cohort from teratogen information service.	2/290 (0.7%)	0/306 (0%) SSRI‐exposed.		Developmental delay. Follow‐up time not specified.
Winterfeld et al.	Cohort from teratogen information service.	2/290 (0.7%)	0/308 (0%) Unexposed.		Developmental delay. Follow‐up time not specified.
Yaris et al.	Cohort/case series from teratogen information service.	7/7	None.		Normal development at 12 months.
Gentile et al., Guclu et al., Kesim et al., Rohde et al., Saks, Sokolover et al., Tonn et al.	Case reports and case series.	20/20	None.		Normal development assessed at 2–24 months.
Viktorin et al.	Cohort from national registers.	2/62 (3.3%)	Background population.	RR 1.53 (95% CI 0.38–6.23)	Autism spectrum disorder at 7–8 years of age. Analyses adjusted for birthdate, maternal and paternal age, mother and father's psychotropic medication overlapping pregnancy, mother and father's psychiatric diagnoses.
Viktorin et al.	Cohort from national registers.		Sub‐analysis restricted to children born to mothers with a diagnosis of depression or anxiety disorder.	RR 1.00 (95% CI 0.14–7.24).
Maternal complications
Palmsten et al.	Cohort study from insurance registers.	14/253	Background pregnancies.	RR 1.05 (95% CI 0.63–1.74) unadjusted. RR 0.81 (95% CI 0.50–1.34) adjusted.	Preeclampsia. Variables in adjusted analysis included year, multiple pregnancies, preeclampsia risk factors, depression severity proxies, comedications and health care utility.
Palmsten et al.	Cohort study from insurance registers.	129 Current exposure (number of cases too low for display)	Background pregnancies.	RR 0.87 (95% CI 0.29–2.66)	Postpartum haemorrhage. Analyses were restricted to women with diagnoses for mood or anxiety disorders. Analyses adjusted several variables including year, age, race, multiple pregnancy, diabetes, coagulopathy, psychiatric diagnoses, comedications, and health care utility.
		0/57 Recent exposure.		No cases in mirtazapine‐exposed.
		135 Past exposure (number of cases too low for display)		RR 0.81 (95% CI 0.50–1.34) adjusted.
Saks, Schwarzer et al.	Case reports.	Preeclampsia (n = 1) Gestational diabetes mellitus (n = 1)
Exposure through breastfeeding
Smit et al.	Case series from psychiatric‐obstetric‐paediatric clinic.	44	None.	No adverse events, nor eating or sleeping problems.
Kristensen et al.	Case series.	8	None.	No adverse events.
				Denver developmental age 101% (95% CI 92–110) of actual age (one infant not assessed).
				Infant dose for mirtazapine and desmethylmirtazapine 1.9% (95% CI 1.1–2.7) of the weight adjusted maternal dose.
Uguz	Case series.	8 Mirtazapine‐paroxetine‐exposed.	None.	No adverse events attributed to mirtazapine. One infant experienced restlessness, but this subsided when paroxetine was stopped.
Aichorn et al., Klier et al, Tonn et al.	Case reports.	3		No adverse events. Two infants had very low mirtazapine concentrations in the blood, but one infant had serum‐mirtazapine 10 ng/mL (adult therapeutic range = 5–100 ng/mL), the infant was heavier than siblings and a better sleeper.

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3.2.1. Spontaneous abortion

Six studies included data on spontaneous abortion. A cohort study by Kjaersgaard et al. ²⁰ included all clinically registered pregnancies in Denmark between 1997 and 2008. The unadjusted relative risk (RR) of spontaneous abortion was 1.73 (95% CI 1.46–2.04) among mirtazapine‐exposed pregnancies compared to unexposed pregnancies. Restricting the analysis to women with a hospital diagnosis of depression resulted in an unadjusted RR of 2.23 (95% CI 1.34–3.70).

Another cohort study conducted by Winterfeld et al. ²¹ including 357 pregnancies from teratology information services reported odds ratios (OR) for spontaneous abortion and stillbirth (composite outcome) of 1.01 (95% CI 0.63–1.61) and 1.34 (95%. CI 0.81–2.20) when comparing mirtazapine‐exposed to SSRI‐exposed and unexposed pregnancies, respectively.

Likewise, Djulus et al. ²² conducted a cohort study based on data from a teratology information service including 104 mirtazapine‐exposed pregnancies. They reported 20/104 (19.2%) spontaneous abortions in the mirtazapine‐exposed pregnancies, 18/104 (17.3%) in pregnancies exposed to other antidepressants, and 11/104 (11%) in the unexposed.

Additionally, data on spontaneous abortion was reported in smaller studies by Ozturk et al., ²³ Yaris et al., ¹⁸ , ¹⁹ , ²⁴ and Biswas et al. ¹⁵

3.2.2. Termination of pregnancy

Four studies reported on elective termination of pregnancy (TOP). TOP in gestational weeks (GW) 12–23 was investigated in a case–control study by Kieler et al. ²⁵ based on Danish, Finnish and Norwegian register data. They found an increased risk of TOP in GW 12–23 for any reason in the mirtazapine‐exposed group compared to unexposed pregnancies (adjusted OR 2.6; 95% CI 1.8–3.9). Winterfeld et al. ²¹ reported five (1.4%) therapeutic TOPs among the 357 mirtazapine‐exposed compared to two (0.6%) and four (1.4%) among the SSRI exposed and the unexposed, respectively. The reason for therapeutic TOP was not specified for all cases and could include maternal factors.

Therapeutic TOP for an unspecified reason was also reported by Djulus et al. ²² Among the 104 participants in each group, six cases were reported in the mirtazapine‐exposed, three in the antidepressant‐exposed, and one in the teratogen‐non‐exposed.

3.2.3. Live birth

Occurrence of live birth was reported in several studies. It should be noted that reasons for pregnancies not ending in live births included stillbirth and elective and therapeutic TOP for unspecified reasons, including maternal factors.

3.2.4. Neonatal outcomes

Gestational age at delivery, preterm birth, birth weight, and small and large for gestational age were comparable between the mirtazapine‐exposed and the control groups in most studies.

3.2.5. Congenital malformations

Ten studies including 1174 pregnancies reported on congenital malformations. A Swedish register‐based study by Källén et al. ²⁶ from 1996 to 2011 included 585 pregnancies exposed to mirtazapine in the first trimester. The OR for severe malformations was 1.10 (95% CI 0.70–1.71) when the mirtazapine‐exposed were compared with the background population. ORs for all cardiac defects and septal defects specifically were 1.06 (95% CI 0.42–2.19) and 1.22 (95% CI 0.45–2.65), respectively. There was no information on whether the analyses were adjusted.

Lennestål et al. ²⁷ also published Swedish register data; however, the investigated pregnancies may overlap with those reported by Källén et al. ²⁶ They included 145 infants born after exposure to mirtazapine monotherapy and nine infants exposed to both mirtazapine and venlafaxine. The rate of malformations was 3.2% in the mirtazapine‐exposed group, compared with 4.7% in the background population.

The above mentioned register‐based case–control study by Kieler et al. ²⁵ reported an increased risk of TOP in GW 12–23 due to fetal anomalies when the mirtazapine‐exposed were compared with the unexposed (adjusted OR 2.2; 95% CI 1.1–4.5; 99% CI 0.9–5.7). Exposure was not restricted to the first trimester, and exclusion of chromosomal and genetic anomalies was not specified.

Winterfeld et al. ²¹ reported no increased risk of major birth defects (excluding chromosomal and genetic causes) after mirtazapine exposure in the first trimester compared with both SSRI‐exposed (OR 0.80; 95% CI 0.35–1.86) and unexposed (OR 1.79; 95% CI 0.64–4.99) pregnancies.

Djulus et al. ²² observed two (2.6%) major congenital malformations (excluding chromosomal and genetic) among 77 mirtazapine‐exposed live births, of which 95% had been exposed in the first trimester, compared with 1/83 (1.2%) and 2/92 (2.2%) among those exposed to other antidepressants and the unexposed, respectively.

Einarson et al. ²⁸ also presenting data from a cohort study from teratogen information services, reported two major malformations among 68 live births (2.9%) after first trimester mirtazapine exposure, compared with 2.6% and 2.7% among all antidepressant‐exposed and unexposed, respectively.

3.2.6. Neonatal complications

Güngör et al. ²⁹ included mirtazapine‐exposed (N = 16), SSRI and mirtazapine‐exposed (N = 18), SSRI‐exposed (N = 40), unexposed with psychiatric diagnosis (N = 23), and healthy control (N = 23) pregnancies from teratology services and found no increased risk of admittance to or longer stay in the neonatal intensive care unit among those exposed to mirtazapine compared to the control groups.

Kieviet et al. ³⁰ reported 18 cases of NAS among the 35 third trimester mirtazapine‐exposed neonates (51%) included in their cohort study. Antidepressant exposure through breastfeeding was associated with a decreased risk of NAS; however, sub‐analyses of breastfeeding were not conducted for the mirtazapine‐exposed separately.

In the case series by Smit et al., ³¹ incidence of NAS was 26% in the 54 infants with third trimester mirtazapine exposure, including one case of respiratory distress. Incidence of NAS was lower in breastfed infants (18.6% vs. 54.5%, p = 0.02). Additional reports on NAS and other neonatal complications are listed in Table 3.

3.2.7. Infant death

One neonatal death and one infant death after mirtazapine exposure in pregnancy were identified. Habermann et al. ¹⁶ described a neonate born in GW 32 who experienced asphyxia and pneumonia, and died 1 day postpartum. The neonate had been exposed to daily mirtazapine 45 mg and quetiapine 100 mg in early pregnancy, and to venlafaxine 300 mg and maternal smoking (15 cigarettes daily) throughout the pregnancy.

Winterfeld et al. ²¹ reported one infant death at 6 months. The child was born with cardiomyopathy after in‐utero exposure to mirtazapine at GA 0–20 weeks.

3.2.8. Offspring development

One study investigating association between mirtazapine exposure in pregnancy and long‐term development was identified. A Swedish nationwide register‐based cohort study by Viktorin et al. ³² followed all children born in 2006–2007 up to 7 or 8 years of age and assessed risk of autism spectrum disorder (ASD). Among the 62 children exposed to mirtazapine in pregnancy, two were diagnosed with ASD, resulting in an adjusted RR 1.53 (95% CI 0.38–6.23) when compared to the background population. An adjusted sub‐analysis restricted to children born to mothers with a diagnosis of depression or anxiety disorder found no increased risk of ASD (RR 1.00; 95% CI 0.14–7.24).

3.2.9. Maternal pregnancy complications

Palmstein et al. investigated the risk of preeclampsia ³³ and postpartum haemorrhage ³⁴ after antidepressant‐exposure in cohort studies based on US insurance data. They found no association between mirtazapine exposure in pregnancy and either outcome.

3.2.10. Infant outcomes after mirtazapine exposure through breastfeeding

Seven studies included data on a total of 63 neonates exposed to mirtazapine through breastfeeding. The largest study by Smit et al. ³¹ included 56 neonates exposed to mirtazapine in‐utero of which 44 were also exposed through breastfeeding. They found no cases of feeding or sleeping problems in the breastfed infants, and incidence of NAS was significantly lower when compared with the non‐breastfed infants (18.6% vs. 54.5%, p = 0.02).

Güngör et al. ²⁹ found that incidence and duration of breastfeeding did not differ significantly between the different groups in their study.

A case series by Kristensen et al. ³⁵ included eight breastfeeding mothers with daily mirtazapine doses ranging from 30 to 120 mg. No adverse events were observed in the eight infants, and their Denver developmental age was 101% (95% CI 92–110) of actual age (n = 7). Infant weight was within the 25th and 75th percentiles (n = 5), and between the 10th and 25th percentiles (n = 3) in those with correspondingly low birth weights. Mirtazapine milk and plasma concentrations were estimated and mean relative infant dose for mirtazapine and desmethylmortazapine was 1.9% (95% CI 1.1–2.7) of the weight adjusted maternal dose.

Another cohort study conducted by Uguz ³⁶ included eight breastfeeding mothers admitted to a perinatal psychiatric clinic that initiated treatment with mirtazapine 15 mg and paroxetine 20 mg daily at 4.3 ± 3.1 weeks postpartum. Restlessness was observed in one infant 5 days after initiation of treatment, but symptoms subsided completely within 48 h of stopping paroxetine with continuation of mirtazapine. No other adverse events were observed in the 3–6 week follow‐up period.

Aichorn et al. ³⁷ described a case where a breastfeeding mother initiated treatment with mirtazapine 30 mg daily at 14 weeks postpartum. After 6 weeks of treatment, normal psychomotor development and no adverse events were observed in the infant. Infant plasma‐mirtazapine was 0.2 ng/mL, compared to therapeutic range 5–100 ng/mL.

Klier et al. ³⁸ described a case where a mother initiated treatment with mirtazapine 22.5 mg daily at 6 weeks postpartum. Infant plasma‐mirtazapine was undetectable 12.5 h post dose. No abnormalities or sedation was observed, and weight gain was consistent with their trajectory prior to mirtazapine treatment.

Finally, a case report by Tonn et al. ³⁹ described an infant whose mother was treated with mirtazapine 15–30 mg daily throughout most of their pregnancy and 15 mg mirtazapine daily while breastfeeding. The infant was heavier at birth and at 2 months old than his 3 siblings had been, and he was sleeping better through the night. Serum mirtazapine was 10 ng/mL in the infant (within the adult therapeutic range), and the authors argue that this could indicate individual differences in elimination rate.

4. DISCUSSION

4.1. Main findings

This systematic review included 41 studies reporting data on maternal, fetal and offspring outcomes after mirtazapine exposure during pregnancy and lactation. All studies were observational; however, they were very heterogeneous in design. Many studies were case reports and small studies.

Overall, most studies did not find mirtazapine exposure to be associated with adverse outcomes; however, the power was low, and most studies had a high risk of bias, predominantly due to confounding by indication.

Few studies contained data on spontaneous abortion. One register study ²⁰ reported an increased risk of spontaneous abortion when the mirtazapine‐exposed were compared with the background population in unadjusted analyses. However, two other studies ²¹ , ²² reported the risk in the mirtazapine‐exposed to be comparable to controls exposed to other antidepressants.

We identified data on 1174 mirtazapine‐exposed pregnancies regarding congenital malformations, and results were conflicting. One register‐based case–control study ²⁵ reported an increased OR for TOP in GW 12–23 for fetal anomalies when the mirtazapine‐exposed were compared with the unexposed in an adjusted analysis. However, exposure was not restricted to the first trimester. Most other studies did not find a significantly increased risk of malformations; however, some found tendencies towards increased risk, while others did not. ²¹ , ²² , ²⁶ , ²⁷ , ²⁸

Gestational age at birth and birth weight were comparable between the mirtazapine‐exposed and the control groups in most studies. However, NAS was reported in 19% to 55% of neonates exposed to mirtazapine in late pregnancy. ³⁰ , ³¹ Breastfeeding was associated with a lower incidence of NAS.

One neonatal death was described, although it was unlikely to be attributable to mirtazapine exposure. ¹⁶

Little data were available on offspring development. One register‐based study ³² investigating the risk of ASD in 7–8 year old children found a tendency towards increased risk in the mirtazapine‐exposed when compared with the background population; however, when the analyses were restricted to children of mothers with depression, the increased risk was not replicated.

Two studies investigated maternal pregnancy complications and observed no increased risk of preeclampsia ³³ or postpartum haemorrhage. ³⁴

We identified data on 63 infants exposed to mirtazapine through breast feeding, ³¹ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ and found no adverse outcomes. Mirtazapine concentration in breastmilk and/or infant plasma were analysed in 11 cases, and all but one found infant plasma concentrations to be below the therapeutic range. ³⁵ , ³⁷ , ³⁸ However, one case report ³⁹ found infant serum‐mirtazapine within the adult therapeutic range, and the infant, who had also been exposed through pregnancy, weighed more and slept more than his siblings.

4.2. Strengths and limitations

This is the largest and most comprehensive review available on mirtazapine exposure in pregnancy and lactation. It includes published data on 2343 exposed pregnancies and 63 infants exposed through lactation and summarises data on all available outcomes.

The broad search strategy including ‘antidepressants’ ensured identification of studies which investigated several antidepressants and reported data on mirtazapine separately. These studies may not have been identified through a search for ‘mirtazapine’ alone, as it may not be mentioned in the title, abstract, or keywords.

We included all study types, and not prespecifying pregnancy and offspring outcomes ensured that we captured unforeseen adverse outcomes.

Overall, the quality of evidence was low, and meta‐analyses were not considered applicable due to the heterogeneity of the studies.

4.3. Interpretation

Overall risk of bias in the included studies was high and the direction of bias was either unpredictable or away from null. Depression is a well‐known risk factor for several adverse pregnancy outcomes ⁴⁰ , ⁴¹ and some studies included adjusted analyses or compared the mirtazapine‐exposed with SSRI‐exposed to adjust for this. However, residual confounding and confounding due to depression severity is still possible. This implies that we should expect to find an increased risk of adverse outcomes. As this is not consistently the case, the results of this review may be interpreted as reassuring for most outcomes.

The above findings are in line with a Danish register‐based study conducted by the present authors which was published after the search for this systematic review was closed. ⁴² In this propensity score matched study including 1945 mirtazapine‐exposed pregnancies, we observed no increased risk of spontaneous abortion, still birth, neonatal death, or congenital malformations.

However, attention should be paid to the risk of NAS after exposure in late pregnancy. Breastfeeding was associated with a lower incidence of NAS; however, whether breastfeeding protects against NAS is uncertain, as development of NAS could also interfere with initiation of breastfeeding.

Similarly, attention should be drawn to neonatal mirtazapine exposure through lactation as one exposed infant had serum‐mirtazapine within adult therapeutic range. This indicates possible individual differences in elimination rate and thus possible side effects in the neonate.

4.4. Conclusion

We found data on from 2343 mirtazapine‐exposed pregnancies and 63 infants exposed through lactation. Overall results were reassuring, but the quality of evidence was generally low, and results were conflicting regarding risk of spontaneous abortion and congenital malformations. These issues make it hard to draw conclusions and highlight the need for further research. Awareness should be drawn to risk of NAS and possible individual elimination rates in neonates exposed through breastfeeding.

AUTHOR CONTRIBUTIONS

Anne Ostenfeld (A, Tonny Studsgaard Petersen, Jon Trærup Andersen, Hanne Brix Westergaard, Lars Henning Pedersen and Ellen Christine Leth Løkkegaard participated in the methodology of the study and Anne Ostenfeld wrote the protocol. Anne Ostenfeld performed the search and, Anne Ostenfeld and Sofie Lyngholm screened and selected the studies. Data extraction and risk of bias assessment was performed by Anne Ostenfeld and Sarah Emilie Christensen. Anne Ostenfeld wrote the first draft of the manuscript, and all authors revised the manuscript and approved the final version.

CONFLICT OF INTEREST STATEMENT

None of the authors have any conflicts of interest to disclose.

Supporting information

Data S1: Search strategy.

ACPS-151-6-s001.docx^{(12.4KB, docx)}

ACKNOWLEDGEMENTS

The study was funded by the Danish Regions’ Medicinal Grant, Nordsjællands Hospital, Department of Clinical Medicine University of Copenhagen, and Kaj og Hermilla Ostenfelds Fond.

Ostenfeld A, Lyngholm S, Christensen SE, et al. Mirtazapine in pregnancy and lactation: A systematic review of adverse outcomes. Acta Psychiatr Scand. 2025;151(1):6‐32. doi: 10.1111/acps.13749

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Data S1: Search strategy.

ACPS-151-6-s001.docx^{(12.4KB, docx)}

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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[acps13749-bib-0002] 2. Gentile S. Untreated depression during pregnancy: short‐ and long‐term effects in offspring. Neuroscience. 2017;342:154‐166. [DOI] [PubMed] [Google Scholar]

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[acps13749-bib-0004] 4. Benjamin S, Doraiswamy PM. Review of the use of mirtazapine in the treatment of depression. Expert Opin Pharmacother. 2011;12(10):1623‐1632. [DOI] [PubMed] [Google Scholar]

[acps13749-bib-0005] 5. Croom KF, Perry CM, Plosker GL. Mirtazapine: a review of its use in major depression and other psychiatric disorders. [DOI] [PubMed]

[acps13749-bib-0006] 6. Cangemi DJ, Kuo B. Practical perspectives in the treatment of nausea and vomiting. J Clin Gastroenterol. 2019;53:170‐178. [DOI] [PubMed] [Google Scholar]

[acps13749-bib-0007] 7. Abramowitz A, Miller ES, Wisner KL. Treatment options for hyperemesis gravidarum. Arch Womens Ment Health. 2017;20(3):363‐372. [DOI] [PMC free article] [PubMed] [Google Scholar]

[acps13749-bib-0008] 8. Omay O, Einarson A. Is mirtazapine an effective treatment for nausea and vomiting of pregnancy? A aase series. J Clin Psychopharmacol. 2017. [cited 2021 Oct 8];37(2):260‐261. Available from: https://pubmed.ncbi.nlm.nih.gov/28129311/ [DOI] [PubMed] [Google Scholar]

[acps13749-bib-0009] 9. Smit M, Dolman KM, Honig A. Mirtazapine in pregnancy and lactation ‐ a systematic review. Eur Neuropsychopharmacol. 2016;26(1):126‐135. Available from: 10.1016/j.euroneuro.2015.06.014 [DOI] [PubMed] [Google Scholar]

[acps13749-bib-0010] 10. Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review and meta‐analysis protocols (prisma‐p) 2015: elaboration and explanation. BMJ. 2015;349:g7647. Available from: www.crd.york.ac.uk/prospero/ [DOI] [PubMed] [Google Scholar]

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[acps13749-bib-0017] 17. Kallen B, Olausson P. Maternal use of selective serotonin re‐uptake inhibitors and persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf. 2008;17:801‐806. [DOI] [PubMed] [Google Scholar]

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[acps13749-bib-0020] 20. Kjaersgaard MIS, Parner ET, Vestergaard M, et al. Prenatal antidepressant exposure and risk of spontaneous abortion – a population‐based study. PLoS One. 2013;8(8):e72095. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[acps13749-bib-0024] 24. Yaris F, Yaris E, Kadioglu M, Ulku C, Kesim M, Kalyoncu NI. Use of polypharmacotherapy in pregnancy: a prospective outcome in a case. Prog Neuro‐Psychopharmacology Biol Psychiatry. 2004;28(3):603‐605. [DOI] [PubMed] [Google Scholar]

[acps13749-bib-0025] 25. Kieler H, Malm H, Artama M, et al. Use of antidepressants and association with elective termination of pregnancy: population based case‐control study. BJOG Int J Obstet Gynaecol. 2015;122:1618‐1624. [DOI] [PubMed] [Google Scholar]

[acps13749-bib-0026] 26. Källén B, Borg N, Reis M. The use of central nervous system active drugs pharmaceutical 2013. Pharmaceuticals. 2013;6(10):1221‐1286. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[acps13749-bib-0031] 31. Smit M, Wennink HJMB, Heres MMHB, Dolman KKM, Honig A. Mirtazapine in pregnancy and lactation: data from a case series. J Clin Psychopharmacol. 2015;35(2):163‐167. [DOI] [PubMed] [Google Scholar]

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PERMALINK

Mirtazapine in pregnancy and lactation: A systematic review of adverse outcomes

Anne Ostenfeld

Sofie Lyngholm

Sarah Emilie Christensen

Tonny Studsgaard Petersen

Jon Trærup Andersen

Hanne Brix Westergaard

Lars Henning Pedersen

Ellen Christine Leth Løkkegaard

Abstract

Introduction

Methods

Results

Conclusions

Summations

Limitations

1. INTRODUCTION

2. MATERIALS AND METHODS

2.1. Eligibility, sources, and search strategy

2.2. Selection process

2.3. Data extraction and risk of bias assessment

2.4. Evidence synthesis

2.5. Specification of relevant exposure and outcomes

3. RESULTS

FIGURE 1.

3.1. Study characteristics

TABLE 1.

TABLE 2.

3.2. Outcomes

TABLE 3.

3.2.1. Spontaneous abortion

3.2.2. Termination of pregnancy

3.2.3. Live birth

3.2.4. Neonatal outcomes

3.2.5. Congenital malformations

3.2.6. Neonatal complications

3.2.7. Infant death

3.2.8. Offspring development

3.2.9. Maternal pregnancy complications

3.2.10. Infant outcomes after mirtazapine exposure through breastfeeding

4. DISCUSSION

4.1. Main findings

4.2. Strengths and limitations

4.3. Interpretation

4.4. Conclusion

AUTHOR CONTRIBUTIONS

CONFLICT OF INTEREST STATEMENT

Supporting information

ACKNOWLEDGEMENTS

DATA AVAILABILITY STATEMENT

REFERENCES

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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